title: TLR4 mediates lung injury and inflammation in intestinal ischemia-reperfusion.
abstract: BACKGROUND
  Splanchnic ischemia is common in critically ill patients, and it can result in injury not only of the intestine but also in distant organs, particularly in the lung. Local inflammatory changes play a pivotal role in the development of acute lung injury after intestinal ischemia, but the underlying molecular mechanisms are not fully understood. We sought to examine the role of Toll-like receptor 4 (TLR4) in the mouse model of intestinal ischemia-reperfusion (I/R)-induced lung injury and inflammation.
  
  
  METHODS
  Adult male TLR4 mutant (C3H/HeJ) mice and TLR4 wild-type (WT) (C3H/HeOuJ) mice were subjected to 40 min of intestinal ischemia by clamping the superior mesenteric artery followed by 6 h of reperfusion. Lung histology was assessed and parameters of pulmonary microvascular permeability, inflammatory cytokine expression, and neutrophil infiltration were measured. Activation of mitogen-activated protein kinases (MAPKs) and the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) in the lungs were also detected.
  
  
  RESULTS
  After intestinal I/R, lungs from TLR4 mutant mice demonstrated a significantly lower histological injury, a marked reduction of epithelial apoptosis associated with the decreased level of cleaved caspase-3 and the increased ratio of Bcl-xL to Bax proteins, and a large reduction in pulmonary vascular permeability and myeloperoxidase (MPO) activity in comparison with WT mice. TLR4 mutant mice also displayed marked decreases in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) expression. Following intestinal I/R, phosporylation of p38 MAPK and activation of NF-κB and AP-1 were significantly inhibited in lung tissue from TLR4 mutant mice compared with WT controls.
  
  
  CONCLUSIONS
  These data suggest that TLR4 plays an important role in the pathogenesis of intestinal I/R-induced acute lung injury and inflammation and that p38 kinase and NF-κB may be involved in TLR4 signaling-mediated lung inflammatory processes during intestinal I/R.
authors.affiliation: Institute of Burn Surgery and Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Dao-Feng
authors.initials: DF
authors.lastname: Ben
authors.forename: Xi-Ya
authors.initials: XY
authors.lastname: Yu
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Ji
authors.forename: De-Yi
authors.initials: DY
authors.lastname: Zheng
authors.forename: Kai-Yang
authors.initials: KY
authors.lastname: Lv
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Zhao-Fan
authors.initials: ZF
authors.lastname: Xia
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000473:pathology; D007422:Intestines / Q000098:blood supply*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D020556:Neutrophil Infiltration; D015427:Reperfusion Injury / Q000150:complications* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D052002:NF-kappa B p50 Subunit; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; C073701:Nfkb1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases